PROJECT SUMMARY Research: Children with sickle cell disease (SCD) face progressive cognitive decline compared to their healthy peers, evidenced by declining IQ, failure to achieve academic milestones, and deficits in executive function. However, the pathophysiological mechanisms underlying cognitive decline are poorly understood, providing a barrier to the development of predictive biomarkers and preventative treatments. Dr. Fields' long-term goal is to understand the pathophysiology of cognitive decline in SCD. Her preliminary studies have shown that oxygen extraction is elevated in children with SCD, suggesting ongoing cerebral metabolic stress. Her central hypothesis is that regional metabolic stress in the deep white matter results in disruption of functional connectivity within specific networks with consequent decline in corresponding cognitive domains. In order to test her hypothesis, she will obtain longitudinal measures of cerebral oxygen metabolism, resting-state functional connectivity and neurocognitive testing to complete the following specific aims: 1) To compare inter- and intra-network connectivity between age-matched children with SCD and healthy siblings unaffected by SCD, 2) To determine if metabolic stress predicts change in functional network architecture in SCD, and 3) To evaluate metabolic stress and disruption of connectivity as predictors of cognitive decline. Completion of these aims will provide insight into the effects of SCD on cognitive development via innovative MRI methods, and develop neuroimaging biomarkers that can risk stratify patients in future clinical trials testing interventions aimed to ameliorate the cognitive effects of sickle cell disease. Candidate: Dr. Fields is a pediatric hematologist whose long-term goal is to become an independent physician-scientist in pediatric hematology focused on studying the debilitating cognitive and neurologic complications suffered by children with sickle cell disease. Her career development plan encompasses formal coursework, institutional and national conferences to facilitate collaboration and one-on-one mentorship and instruction from Dr. Jin-Moo Lee in cerebral metabolism, Dr. Bradley Schlaggar in acquisition, processing and application of BOLD imaging, Dr. Allison King in neuropsychology and the cognitive implications of sickle cell disease and Dr. Amber Salter in biostatistics. This training plan will enable Dr. Fields to use novel imaging modalities to understand the pathophysiology of cognitive decline in SCD. Environment: Washington University (WU) is world-renowned for neuroimaging research and resources. The specialized MR sequence used to measure oxygen extraction fraction in this proposal was developed at WU by Dr. Hongyu An, a consultant for this proposal. Positron emission tomography imaging was developed at WU, and many of the canonical resting state networks were discovered at WU. In addition to WU leading the Human Connectome Project, directed by Drs. David Van Essen and Deanna Barch, some of the most respected neuroscientists in the world are found at WU, including Drs. Marcus Raichle, Steven Petersen, and my mentors, Drs. Jin-Moo Lee and Bradley Schlaggar.